rs149946088

Variant names:

• chr3-179148542-C-T
• rs149946088
• NM_006218.4:c.-138C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_006218.4(PIK3CA):​c.-138C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0036 in 152,350 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (0 hom.)
• Consequence: PIK3CA NM_006218.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.808
• Publications: 1 publications found

Genes affected

PIK3CA (HGNC:8975): (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) Phosphatidylinositol 3-kinase is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P2. This gene has been found to be oncogenic and has been implicated in cervical cancers. A pseudogene of this gene has been defined on chromosome 22. [provided by RefSeq, Apr 2016]

PIK3CA Gene-Disease associations (from GenCC):

• overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• megalencephaly-capillary malformation-polymicrogyria syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• vascular malformation

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden syndrome 5

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 3-179148542-C-T is Benign according to our data. Variant chr3-179148542-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 802024.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00361 (548/151746) while in subpopulation NFE AF = 0.00596 (404/67832). AF 95% confidence interval is 0.00548. There are 1 homozygotes in GnomAd4. There are 255 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 548 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3CA	NM_006218.4	c.-138C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 21	ENST00000263967.4	NP_006209.2
PIK3CA	NM_006218.4	c.-138C>T		5_prime_UTR_variant	Exon 1 of 21	ENST00000263967.4	NP_006209.2
PIK3CA	XM_006713658.5	c.-77+323C>T		intron_variant	Intron 1 of 20		XP_006713721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3CA	ENST00000263967.4	c.-138C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 21	2	NM_006218.4	ENSP00000263967.3
PIK3CA	ENST00000263967.4	c.-138C>T		5_prime_UTR_variant	Exon 1 of 21	2	NM_006218.4	ENSP00000263967.3
PIK3CA	ENST00000477735.1	c.-77+323C>T		intron_variant	Intron 1 of 1	4		ENSP00000418145.1
PIK3CA	ENST00000643187.1	c.-138C>T		upstream_gene_variant				ENSP00000493507.1

Frequencies

GnomAD3 genomes AF: 0.00361 AC: 548 AN: 151638 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000605

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.000920

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00563

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00596

Gnomad OTH AF: 0.00192

GnomAD4 exome AF: 0.00166 AC: 1 AN: 604 Hom.: 0 Cov.: 0 AF XY: 0.00223 AC XY: 1 AN XY: 448

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 10

American (AMR) AF: 0.00 AC: 0 AN: 8

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8

East Asian (EAS) AF: 0.00 AC: 0 AN: 18

South Asian (SAS) AF: 0.00 AC: 0 AN: 124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00236 AC: 1 AN: 424

Other (OTH) AF: 0.00 AC: 0 AN: 10

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00361 AC: 548 AN: 151746 Hom.: 1 Cov.: 31 AF XY: 0.00344 AC XY: 255 AN XY: 74180

African (AFR) AF: 0.000603 AC: 25 AN: 41466

American (AMR) AF: 0.000919 AC: 14 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00563 AC: 59 AN: 10476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00596 AC: 404 AN: 67832

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.00707 Hom.: 1

Bravo AF: 0.00313

Asia WGS AF: 0.000289 AC: 1 AN: 3468

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cowden syndrome 1 Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Uncertain	0.98
PhyloP100		0.81
PromoterAI		-0.036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.4
Mutation Taster		=279/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs149946088; hg19: chr3-178866330;